Project Summary The development and formation of normal and abnormal vasculature is of critical importance to both normal biology and disease pathogenesis. Recent studies from our and other laboratories have demonstrated the importance of syndecans in regulation of heparan-binding growth factors signaling on endothelial cells. Yet, despite the impressive degree of syndecan- dependent regulation of VEGF signaling, there is a very limited understanding of how this is accomplished. In preliminary studies, we have observed abnormal developmental angiogenesis in mice missing syndecan-2 and abnormal lymphatic morphogenesis in mice missing syndecan- 4. Furthermore, signaling studies point to VEGFA specificity for syndecan-2 and VEGFC specificity for syndecan-4. We propose to determine relative contributions of Syndecan-2 and Syndecan-4 to, respectively, VEGFR2-driven angiogenesis and VEGFR3-driven lymphangiogenesis both in development and in adult settings. The understanding of accounts for these signaling specificities would open-up the possibility of selectively targeting angiogenesis vs. lymphangiogenesis in a number of settings and, be, potentially, of tremendous clinical significance.